title: Receptors for non-MHC ligands contribute to uterine natural killer cell activation during pregnancy in mice.
abstract: BACKGROUND
  Activated uterine natural killer (uNK) cells are abundant in early human and mouse decidual basalis. In mice, distinct uNK cell subsets support early endothelial tip cell induction, the pruning of new vessels and initiation of spiral arterial modification. While genetic studies indicate that NK/uNK cell activation via receptors recognizing Class I MHC-derived peptides promotes human pregnancy, roles for other activation receptors expressed by NK cells, such as the aryl hydrocarbon receptor (AHR) and natural cytotoxicity receptors (NCR) are undefined in human or mouse pregnancies.
  
  
  METHODS
  Expression of AHR and NCR1 (ortholog of human NKp46) by gestation day (gd)10.5 mouse uNK cell subsets was measured by quantitative real-time RT-PCR. Early implantation sites from mice lacking expression of either receptor were examined histologically.
  
  
  RESULTS
  Gd10.5 uNK cell subsets, separated by reactivity to Dolichos biflorus agglutinin lectin, differed in relative transcript abundance for Ahr and Ncr1. Quantitative histology revealed that, in comparison to C57BL/6 controls, implant sites from gd10.5 Ahr(-/-) and gd6.5-12.5 UkCa:B6.Ncr1(Gfp/Gfp) mice had normal uNK cell abundance but the uNK cells were smaller than normal and unable to trigger spiral arterial remodeling. Whole mount immunohistochemistry comparisons of viable, gd6.5-8.5 Ncr1(Gfp/Gfp) and C57BL/6 implant sites revealed deficits in implant site angiogenesis and conceptus growth in Ncr1(Gfp/Gfp).
  
  
  CONCLUSIONS
  In mice, activation of AHR and of NCR1 by endogenous, as yet undefined ligands, contributes to uNK cell activation/maturation and angiogenic functions during early to mid-gestation pregnancy. MHC-independent activation of uNK cells also likely makes critical contributions to human pregnancy success.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada K7L3N6.
authors.forename: A M
authors.initials: AM
authors.lastname: Felker
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: W G
authors.initials: WG
authors.lastname: Foster
authors.forename: B A
authors.initials: BA
authors.lastname: Croy
mesh_terms: D000373:Agglutinins / Q000494:pharmacology; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D003656:Decidua / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D010064:Embryo Implantation / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D019891:Leukopoiesis / Q000187:drug effects; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010929:Placentation / Q000187:drug effects; D037121:Plant Lectins / Q000494:pharmacology; D011247:Pregnancy; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D000373:Agglutinins; D000950:Antigens, Ly; D051792:Basic Helix-Loop-Helix Proteins; D008024:Ligands; D055627:Natural Cytotoxicity Triggering Receptor 1; D037121:Plant Lectins; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C118384:Ncr1 protein, mouse; C036554:dolichos biflorus agglutinin
keywords: Arylhydrocarbon receptor; Decidua; Histology; Natural cytotoxicity receptor; Reproductive immunology; Spiral artery remodeling